The studies presented in this proposal are aimed at further exploration of the acetaminophen hepatotoxicity hamster model as a basis for further understanding of the general phenomenon of drug-induced liver injury. This application is organized into four projects dealing with different aspects of the problem: Project 1: To examine further the kinetic and pharmacokinetic relationship between acetaminophen metabolism and formation of its toxic metabolite as a basis for: a) possible drug-drug interactions in the overdose situation, b) the development of more specific experimental tools to be used for establishing new animal models for drug cytotoxicity, c) the examination of the mechanism of the current "best" therapy as well as possible alternate therapies for acetaminophen overdosage, as a guide to improvement of this therapy, and d) the examination of the applicability, in man, of the concept of competing toxic and nontoxic processes as a determinant of susceptibility to drug-induced hepatotoxicity. Project 2: To examine several aspects of the relationship between the structure of acetaminophen and analogues and their hepatotoxicity. Project 3: To examine the effect of factors which may alter hepatic glutathione capacity either before, or as a consequence of therapy of, acetaminophen overdosage, and Project 4: To test further the postulate that an animal model for hepatotoxic drugs in man may be developed by suitable manipulation in vivo of competing toxic and nontoxic pathways of the drug's metabolism, and to examine the underlying mechanisms.